Distinct structural classes of activating FOXA1 alterations in prostate cancer progression [ChIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123618 | GEO | 2018/12/12
REPOSITORIES: GEO
Similar Datasets
Project description:Expression profiles of 22RV1 prostate cancer cells following FOXA1 genetic engineering and or TLE3 knock-down
2018-12-12 | GSE123619 | GEO
Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.
2023-11-07 | GSE214756 | GEO
Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.
2023-11-07 | GSE214754 | GEO
Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.
2023-11-07 | GSE214753 | GEO
Project description:AbtractForkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3-8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9-11 and oncogenic12-14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.
| S-EPMC6661908 | biostudies-literature
Project description:Distinct structural classes of activating FOXA1 alterations in prostate cancer progression
| PRJNA509420 | ENA
Project description:Previous studies have shown that FOXA1 defines prostatic AR binding events, the underlying mechanisms of which, however, are incompletely understood. To test whether ectopic AR and FOXA1 can activate AR target genes, we performed adenoviral of LacZ, AR, FOXA1 or AR+FOXA1 proteins in DU145 cells, followed by microarray analysis of these cells.
2014-06-02 | E-GEOD-54991 | biostudies-arrayexpress
Project description:FoxA1 has been shown critical for prostate development and prostate-specific gene expression regulation. In addition to its well-established role as an AR pioneering factor,several studies have recently revealed significant AR binding events in prostate cancer cells with FoxA1 knockdown. Furthermore, the role of FoxA1 itself in prostate cancer has not been carefully examined. Thus, it is important to understand the role of FoxA1 in prostate cancer and how it interacts with AR signaling. ChIP-Seq examination of AR and FoxA1 binding sites, FAIRE-seq detection of open chromatin genomic regions in DU145 AR +/- FOXA1 cells
2014-06-02 | E-GEOD-47987 | biostudies-arrayexpress
Project description:FoxA1 has been shown critical for prostate development and prostate-specific gene expression regulation. In addition to its well-established role as an AR pioneering factor,several studies have recently revealed significant AR binding events in prostate cancer cells with FoxA1 knockdown. Furthermore, the role of FoxA1 itself in prostate cancer has not been carefully examined. Thus, it is important to understand the role of FoxA1 in prostate cancer and how it interacts with AR signaling. To address these questions, we generated LNCaP cells with stable FoxA1 knockdown. We performed AR/FoxA1 ChIP-seq and microarray analysis of these cells. ChIP_Seq examination of AR and FoxA1 binding sites in LNCaP shCtrl and shFoxA1 cells
2014-06-02 | E-GEOD-37345 | biostudies-arrayexpress
Project description:AR is tightly regulated by many transcriptional cofactors, including key pioneer factor such as FOXA1 and GATA2. While FOXA1 was recently shown to be able to redistribute AR across the genome, how GATA2 regulates AR cistrome has not been carefully investigated. Here, we report that, unlike FOXA1, GATA2 is unable to reprogram AR, but instead it enhances AR program by inducing AR expression and augmenting AR co-occupancy, thereby acting as a pure AR coactivator, rather than a pioneer factor. On the other hand, AR co-occupancy enhances both GATA2 and FOXA1 binding on the chromatin, forming a positive feedback loop. Importantly, we found that FOXA1 is also capable of reprogramming GATA2 by recruiting GATA2 from GATA motif to FKHD-containing regions, being analogous to its pioneering effect on AR signaling. By contrast, GATA2 simply acts as a co-activator of FOXA1 with a lack of pioneering ability. ChIP_Seq examination of AR, FoxA1 and GATA2 binding sites in LNCaP and DU145 cells
2016-01-11 | E-GEOD-69043 | biostudies-arrayexpress